ApoE-isoform-dependent cellular uptake of amyloid-β is mediated by lipoprotein receptor LR11/SorLA

Yajima, Ryuji; Tokutake, Takayoshi; Koyama, Akira; Kasuga, Kensaku; Tezuka, Toshiki; Nishizawa, Masatoyo; Ikeuchi, Takeshi

doi:10.1016/j.bbrc.2014.11.111

Cited by 42 publications

(52 citation statements)

References 23 publications

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“…APP can be cleaved to Aβ (Fig. 5, magenta) when it is trapped in endosomes that contain β-secretase (BACE) 143 , a process exacerbated by the APOE E4 genotype 144,145 . The aggregation of pTau on microtubules may similarly trap APP-containing endosomes and lead to the generation of Aβ oligomers.…”

Section: Potential Relevance To Degeneration In Alzheimer’s Diseasementioning

confidence: 99%

“…Magenta: APP is cleaved to Aβ when it is trapped in endosomes that contain β-secretase (BACE)—for example, when there is interference with APP endosomal trafficking 143 . Indeed, the increased risk of Alzheimer’s disease conferred by the apoE4 variant is thought to involve increased localization of APP into endosomes 145 . The aggregation of pTau on microtubules may similarly trap APP-containing endosomes and lead to the increased generation of Aβ oligomers.…”

Section: Figurementioning

confidence: 99%

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Stress weakens prefrontal networks: molecular insults to higher cognition

2015

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A variety of cognitive disorders are worsened by stress exposure and involve dysfunction of the newly evolved prefrontal cortex (PFC). Exposure to acute, uncontrollable stress increases catecholamine release in PFC, reducing neuronal firing and impairing cognitive abilities. High levels of noradrenergic α1-adrenoceptor and dopaminergic D1 receptor stimulation activate feedforward calcium–protein kinase C and cyclic AMP–protein kinase A signaling, which open potassium channels to weaken synaptic efficacy in spines. In contrast, high levels of catecholamines strengthen the primary sensory cortices, amygdala and striatum, rapidly flipping the brain from reflective to reflexive control of behavior. These mechanisms are exaggerated by chronic stress exposure, where architectural changes lead to persistent loss of PFC function. Understanding these mechanisms has led to the successful translation of prazosin and guanfacine for treating stress-related disorders. Dysregulation of stress signaling pathways by genetic insults likely contributes to PFC deficits in schizophrenia, while age-related insults initiate interacting vicious cycles that increase vulnerability to Alzheimer’s degeneration.

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Section: Potential Relevance To Degeneration In Alzheimer’s Diseasementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Stress weakens prefrontal networks: molecular insults to higher cognition

2015

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“…Additionally, it is still unclear to which extent SORL1 is implicated in the development of AD in patients carrying the APOE4 allele(s). In this regard, recent reports have suggested that the ApoE-isoform-dependent differences in modulating the cellular A β uptake may be related to SORL1 expression and activity [36]. …”

Section: Discussionmentioning

confidence: 99%

Sortilin-Related Receptor Expression in Human Neural Stem Cells Derived from Alzheimer’s Disease Patients Carrying the APOE Epsilon 4 Allele

et al. 2017

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Alzheimer's disease (AD) is the most common form of dementia in the elderly; important risk factors are old age and inheritance of the apolipoprotein E4 (APOE4) allele. Changes in amyloid precursor protein (APP) binding, trafficking, and sorting may be important AD causative factors. Secretase-mediated APP cleavage produces neurotoxic amyloid-beta (Aβ) peptides, which form lethal deposits in the brain. In vivo and in vitro studies have implicated sortilin-related receptor (SORL1) as an important factor in APP trafficking and processing. Recent in vitro evidence has associated the APOE4 allele and alterations in the SORL1 pathway with AD development and progression. Here, we analyzed SORL1 expression in neural stem cells (NSCs) from AD patients carrying null, one, or two copies of the APOE4 allele. We show reduced SORL1 expression only in NSCs of a patient carrying two copies of APOE4 allele with increased Aβ/SORL1 localization along the degenerated neurites. Interestingly, SORL1 binding to APP was largely compromised; this could be almost completely reversed by γ-secretase (but not β-secretase) inhibitor treatment. These findings may yield new insights into the complex interplay of SORL1 and AD pathology and point to NSCs as a valuable tool to address unsolved AD-related questions in vitro.

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“…Experimental studies suggest that the proteins encoded by the APOE and SORL1 genes functionally interact [36]. By binding to the complement type repeats of the SORL1 protein, ApoE4 reduced the AβPP-binding-capacity of SORL1 [37].…”

Section: Discussionmentioning

confidence: 99%

“…By binding to the complement type repeats of the SORL1 protein, ApoE4 reduced the AβPP-binding-capacity of SORL1 [37]. Furthermore, overexpression of SORL1 increases the uptake of extracellular Aβ in an ApoE-isoform-dependent manner, most efficiently in the presence of the ɛ 4 isoform [36]. Therefore, the clearance of Aβ is expected to be more dependent on SORL1 expression in APOE - ɛ 4 carriers than in individuals with no APOE - ɛ 4 alleles.…”

Section: Discussionmentioning

confidence: 99%

Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer’s Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity

Louwersheimer

Cohn-Hokke

Pijnenburg

et al. 2017

JAD

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Background: The major genetic risk factor for late onset Alzheimer’s disease (AD) is the APOE-ɛ4 allele. However, APOE-ɛ4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants.Objective: To identify genetic factors that, next to APOE-ɛ4 homozygosity, contribute to the development of AD.Methods: We identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1, PSEN2, or APP. We collected DNA from four affected and seven unaffected family members and performed exome sequencing on DNA from three affected and one unaffected family members.Results: All affected family members were homozygous for the APOE-ɛ4 allele. Statistical analysis revealed that AD onset in this family was significantly earlier than could be expected based on APOE genotype and gender. Next to APOE-ɛ4 homozygosity, we found that all four affected family members carried a rare variant in the VPS10 domain of the SORL1 gene, associated with AβPP processing and AD risk. Furthermore, three of four affected family members carried a rare variant in the TSHZ3 gene, also associated with AβPP processing. Affected family members presented between 61 and 74 years, with variable presence of microbleeds/cerebral amyloid angiopathy and electroencephalographic abnormalities.Conclusion: We hypothesize that next to APOE-ɛ4 homozygosity, impaired SORL1 protein function, and possibly impaired TSHZ3 function, further disturbed Aβ processing. The convergence of these genetic factors over several generations might clarify the increased AD penetrance and the autosomal dominant-like inheritance pattern of AD as observed in this family.

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ApoE-isoform-dependent cellular uptake of amyloid-β is mediated by lipoprotein receptor LR11/SorLA

Cited by 42 publications

References 23 publications

Stress weakens prefrontal networks: molecular insults to higher cognition

Stress weakens prefrontal networks: molecular insults to higher cognition

Sortilin-Related Receptor Expression in Human Neural Stem Cells Derived from Alzheimer’s Disease Patients Carrying the APOE Epsilon 4 Allele

Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer’s Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity

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